Historically, many methods have been developed to improve the delivery of drugs to their target organs and to allow drug release over prolonged periods of time. These controlled drug release methods generally involved the use of carrier systems to carry the drug to the vicinity of its target organ (usually the blood stream) where it released on initial dose of the drug as rapidly as possible to achieve the desired therapeutic level and then provided for a further sustained release of the drug at a desired substantially constant rate to maintain the same therapeutic level of the drug during the predetermined period of activity.
Our prior co-pending application Ser. No. 07/306,170, now U.S. Pat. No. 5,013,552 which is incorporated herein by reference discloses a composition of matter comprising a plant pollen grain, the pores or interstices of which are loaded (impregnated) with a biologically active substance, which loaded substance is releasable in or on a plant or an animal and is foreign to a naturally occurring pollen grain. That invention was, in part, based on our discovery that pollen grains could be modified by removing their natural contents and substituting or loading therein a variety of biologically active materials, such as drugs, chemicals and other pharmacologically active substances, which could then be delivered to target organs, fluids, sites, surfaces or areas in or on plants and animals, where the substance contained within the pollen grains would be released in a manner akin to the normal release of the natural contents of pollen grains in the pollination process. The use of loaded pollen grains as delivery vehicles was found to be particularly useful in the transfer of molecules, and especially large macromolecules, into the blood stream, since they usually cannot otherwise be absorbed therein or reach the circulatory system. Since the rugged or spiny surface of each pollen grain adheres to tissue surfaces and particularly to mucous membranes, the loaded pollen grains disclosed in said prior application were assured of remaining in contact with the target organ for prolonged periods of time during which the active substance was released in situ. However, no other provision was made to prolong or otherwise control the release of the loaded substance contained therein. It has also been found that spores may be utilized in the same fashion as plant pollen grains.
A number of investigators have observed, though, that the effects of certain hormones, including insulin and native ganodotropin releasing hormone (GNRH), are a function of the rate of change in their serum level rather than in their absolute level. Sensitive assay techniques, such as radioimmunoassay, now show that many natural hormones are released in pulses rather than at a steady rate. It has been found that such pulses occur about every 12-15 minutes for insulin and about every 6 minutes for GNRH. These observations may explain why in cell-free preparations, the initial response to a particular hormone disappears in the continued presence of the stimulating hormone. In in vitro experiments, if the supernatant liquid still containing the hormone to which no response is being elicited is added to a naive preparation (one not previously exposed to the hormone), a response to the supernatant liquid is again observed. This suggests that the hormone is still active and that the rate of change in its concentration may be more important in eliciting a response than its absolute level in the surrounding medium.